Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHCO2F0)

• DOT Name: T-box transcription factor T (TBXT)
• Synonyms: Brachyury protein; Protein T
• Gene Name: TBXT
• Related Disease:
  Autoimmune disease
  Chordoma
  Graves disease
  Idiopathic thrombocytopenic purpura
  Neural tube defect
  Neural tube defects, susceptibility to
  Substance abuse
  Limb-girdle muscular dystrophy
  Sacral agenesis-abnormal ossification of the vertebral bodies-persistent notochordal canal syndrome
  Adenocarcinoma
  Carcinoma
  Goiter
  Neoplasm
  Squamous cell carcinoma
• UniProt ID: TBXT_HUMAN
• PDB ID: 5QRF ; 5QRG ; 5QRH ; 5QRI ; 5QRJ ; 5QRK ; 5QRL ; 5QRM ; 5QRN ; 5QRO ; 5QRP ; 5QRQ ; 5QRR ; 5QRS ; 5QRT ; 5QRU ; 5QRV ; 5QRW ; 5QRX ; 5QRY ; 5QRZ ; 5QS0 ; 5QS1 ; 5QS2 ; 5QS3 ; 5QS4 ; 5QS5 ; 5QS6 ; 5QS7 ; 5QS8 ; 5QS9 ; 5QSA ; 5QSB ; 5QSC ; 5QSD ; 5QSE ; 5QSF ; 5QSG ; 5QSH ; 5QSI ; 5QSJ ; 5QSK ; 5QSL ; 5QT0 ; 6F58 ; 6F59 ; 6ZU8 ; 7ZK2 ; 7ZKF ; 7ZL2 ; 8A10 ; 8A7N ; 8CDN
• Pfam ID: PF00907
• Sequence:
  MSSPGTESAGKSLQYRVDHLLSAVENELQAGSEKGDPTERELRVGLEESELWLRFKELTN
  EMIVTKNGRRMFPVLKVNVSGLDPNAMYSFLLDFVAADNHRWKYVNGEWVPGGKPEPQAP
  SCVYIHPDSPNFGAHWMKAPVSFSKVKLTNKLNGGGQIMLNSLHKYEPRIHIVRVGGPQR
  MITSHCFPETQFIAVTAYQNEEITALKIKYNPFAKAFLDAKERSDHKEMMEEPGDSQQPG
  YSQWGWLLPGTSTLCPPANPHPQFGGALSLPSTHSCDRYPTLRSHRSSPYPSPYAHRNNS
  PTYSDNSPACLSMLQSHDNWSSLGMPAHPSMLPVSHNASPPTSSSQYPSLWSVSNGAVTP
  GSQAAAVSNGLGAQFFRGSPAHYTPLTHPVSAPSSSGSPLYEGAAAATDIVDSQYDAAAQ
  GRLIASWTPVSPPSM
• Function: Involved in the transcriptional regulation of genes required for mesoderm formation and differentiation. Binds to a palindromic T site 5'-TTCACACCTAGGTGTGAA-3' DNA sequence and activates gene transcription when bound to such a site.
• Tissue Specificity: Detected in testis, but not in other, normal tissues. Detected in lung tumors (at protein level).
• Reactome Pathway:
  Germ layer formation at gastrulation (R-HSA-9754189)
  Epithelial-Mesenchymal Transition (EMT) during gastrulation (R-HSA-9758919)
  Formation of paraxial mesoderm (R-HSA-9793380)
  Formation of axial mesoderm (R-HSA-9796292)
  Formation of definitive endoderm (R-HSA-9823730)
  Cardiogenesis (R-HSA-9733709)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autoimmune disease	DISORMTM	Strong	Altered Expression	[1]
Chordoma	DISCHJE7	Strong	Autosomal dominant	[2]
Graves disease	DISU4KOQ	Strong	Altered Expression	[3]
Idiopathic thrombocytopenic purpura	DISFKGJU	Strong	Altered Expression	[4]
Neural tube defect	DIS5J95E	Strong	Biomarker	[5]
Neural tube defects, susceptibility to	DISHA84K	Strong	Genetic Variation	[6]
Substance abuse	DIS327VW	Strong	Genetic Variation	[7]
Limb-girdle muscular dystrophy	DISI9Y1Z	moderate	Genetic Variation	[8]
Sacral agenesis-abnormal ossification of the vertebral bodies-persistent notochordal canal syndrome	DIS4MD8H	Supportive	Autosomal recessive	[9]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[10]
Carcinoma	DISH9F1N	Limited	Altered Expression	[10]
Goiter	DISLCGI6	Limited	Biomarker	[11]
Neoplasm	DISZKGEW	Limited	Altered Expression	[12]
Squamous cell carcinoma	DISQVIFL	Limited	Altered Expression	[10]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	T-box transcription factor T (TBXT) increases the response to substance of Arsenic.	[21]

10 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of T-box transcription factor T (TBXT).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin affects the expression of T-box transcription factor T (TBXT).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of T-box transcription factor T (TBXT).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of T-box transcription factor T (TBXT).	[16]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of T-box transcription factor T (TBXT).	[17]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of T-box transcription factor T (TBXT).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of T-box transcription factor T (TBXT).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of T-box transcription factor T (TBXT).	[19]
SB-431542	DM0YOXQ	Preclinical	SB-431542 affects the expression of T-box transcription factor T (TBXT).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of T-box transcription factor T (TBXT).	[17]

References

• [1] Association of TBX21 promoter polymorphisms with type 1 autoimmune hepatitis in a Chinese population.Hum Immunol. 2011 Jan;72(1):69-73. doi: 10.1016/j.humimm.2010.10.019. Epub 2010 Oct 25.
• [2] A common single-nucleotide variant in T is strongly associated with chordoma. Nat Genet. 2012 Nov;44(11):1185-7. doi: 10.1038/ng.2419. Epub 2012 Oct 14.
• [3] Thyrotoxic crisis as an acute clinical presentation in a child.BMJ Case Rep. 2018 Mar 23;2018:bcr2017222850. doi: 10.1136/bcr-2017-222850.
• [4] Aberrant expression of RUNX3 in patients with immune thrombocytopenia.Int Immunopharmacol. 2015 Sep;28(1):252-6. doi: 10.1016/j.intimp.2015.06.008. Epub 2015 Jun 17.
• [5] Human T and risk for neural tube defects.J Med Genet. 2002 Mar;39(3):E14. doi: 10.1136/jmg.39.3.e14.
• [6] Autozygome and high throughput confirmation of disease genes candidacy. Genet Med. 2019 Mar;21(3):736-742. doi: 10.1038/s41436-018-0138-x. Epub 2018 Sep 21.
• [7] Prior Exposure to Intimate Partner Violence Associated With Less HIV Testing Among Young Women.J Interpers Violence. 2021 Mar;36(5-6):NP2848-NP2867. doi: 10.1177/0886260518768564. Epub 2018 Apr 13.
• [8] Interaction of synthetic peptides corresponding to the scaffolding domain of Caveolin-3 with model membranes.Biopolymers. 2006;84(6):615-24. doi: 10.1002/bip.20595.
• [9] Mutations in the T (brachyury) gene cause a novel syndrome consisting of sacral agenesis, abnormal ossification of the vertebral bodies and a persistent notochordal canal. J Med Genet. 2014 Feb;51(2):90-7. doi: 10.1136/jmedgenet-2013-102001. Epub 2013 Nov 19.
• [10] Brachyury, a driver of the epithelial-mesenchymal transition, is overexpressed in human lung tumors: an opportunity for novel interventions against lung cancer.Clin Cancer Res. 2012 Jul 15;18(14):3868-79. doi: 10.1158/1078-0432.CCR-11-3211. Epub 2012 May 18.
• [11] Monitoring and Evaluation of Thyroid Function Tests, Serum Electrolytes and Creatinine Levels Before and After 131I Therapy.Endocr Metab Immune Disord Drug Targets. 2020;20(3):419-424. doi: 10.2174/1871530319666190829163413.
• [12] Immunopathologic characteristics of nasal polyps in adult Koreans: A single-center study.Am J Rhinol Allergy. 2017 May 1;31(3):168-173. doi: 10.2500/ajra.2017.31.4423.
• [13] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [14] Molecular characterization of a toxicological tipping point during human stem cell differentiation. Reprod Toxicol. 2020 Jan;91:1-13. doi: 10.1016/j.reprotox.2019.10.001. Epub 2019 Oct 7.
• [15] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [16] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [17] Bisphenol A Represses Dopaminergic Neuron Differentiation from Human Embryonic Stem Cells through Downregulating the Expression of Insulin-like Growth Factor 1. Mol Neurobiol. 2017 Jul;54(5):3798-3812. doi: 10.1007/s12035-016-9898-y. Epub 2016 Jun 7.
• [18] A human embryonic stem cell-based model for benzo[a]pyrene-induced embryotoxicity. Reprod Toxicol. 2019 Apr;85:26-33. doi: 10.1016/j.reprotox.2019.01.008. Epub 2019 Jan 16.
• [19] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [20] Activin/nodal signaling switches the terminal fate of human embryonic stem cell-derived trophoblasts. J Biol Chem. 2015 Apr 3;290(14):8834-48.
• [21] Gene expression levels in normal human lymphoblasts with variable sensitivities to arsenite: identification of GGT1 and NFKBIE expression levels as possible biomarkers of susceptibility. Toxicol Appl Pharmacol. 2008 Jan 15;226(2):199-205. doi: 10.1016/j.taap.2007.09.004. Epub 2007 Sep 15.